CN107998399B - Cyclosporine compound eye drops and preparation method thereof - Google Patents
Cyclosporine compound eye drops and preparation method thereof Download PDFInfo
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Abstract
The compound eye drop consists of cyclosporin, anti-inflammatory or antibiotic medicine, surfactant, stabilizer, thickener, isoosmotic regulator, pH regulator and water or oil, and is prepared in the form of suspension or emulsion through one or two of high pressure homogenization and wet grinding. The ciclosporin compound eye drops provided by the invention have good ocular tolerance and high drug utilization rate, can effectively increase tear secretion of xerophthalmia, stabilize lacrimal film, synergistically play the anti-inflammatory and antibiotic drug immunoregulation functions of inflammation resistance and ciclosporin, can effectively treat xerophthalmia, and have better treatment effect compared with the single administration of ciclosporin.
Description
Technical Field
The invention relates to a compound medicinal preparation and a preparation method thereof, in particular to a cyclosporin compound eye drop and a preparation method thereof, belonging to the field of medicines.
Background
With the rapid development and popularization of video terminals such as mobile phones and computers, the incidence of dry eye diseases clinically manifested as discomfort of eyes, instability of tear film, visual disturbance and ocular surface inflammation increases year by year. The global incidence of the xerophthalmia is reported to be 5.5% -33.7%, while the incidence of the xerophthalmia is 21% -30% in China, the incidence is high, and the xerophthalmia brings great influence on the life of patients. Research shows that xerophthalmia is caused by lacrimal secretion of aqueous layer, secretion of lipid layer, insufficient secretion of mucin layer, excessive evaporation of tears, uneven distribution of lacrimal film, inflammation, etc.
At present, artificial tears are mostly adopted clinically to treat xerophthalmia, and because the artificial tears contain ions, pH values and mucin components which are the same as tears of normal people, and the osmotic pressure and the viscosity are very close to each other, the symptoms such as dry eyes, foreign body burning sensation, eye swelling pain and the like can be improved, the eye surface lubrication and humidity can be improved, the inflammation and nutrition can be relieved, and meanwhile, the tear secretion can be increased and the tear rupture time can be prolonged. Although artificial tears may ameliorate the symptoms of dry eye, there is no evidence that they may address the inflammation associated with dry eye. The 0.05% cyclosporine emulsion eye drops (Restasis) sold in foreign markets can effectively treat various types of xerophthalmia through the modes of immunosuppression, reduction of inflammatory reaction, increase of goblet cell density and mucin secretion level, increase of tear flow and the like, are widely applied in European and American countries in clinic, but do not enter the domestic market, and domestic manufacturers do not produce the same product.
Cyclosporin eye drops have a certain therapeutic effect on dry eye, but the final therapeutic effect is still unsatisfactory. The third-stage validated clinical trial of Seciera (cyclosporine eye drops) of indian sun pharmaceutical limited in 1 month 2017 has yielded good results. Seciera is a novel nano preparation with 0.09% of cyclosporine concentration, and has smaller granularity, higher concentration and faster effect than the existing dry eye resistant cyclosporine eye drops. The product is currently being developed and popularized for global markets such as the united states, europe, and japan as well as a number of emerging countries.
Patent CN103735495B discloses a cyclosporine gel and a preparation method thereof, patent CN101181227B discloses a cyclosporine solid lipid nanoparticle preparation and a preparation method thereof, patent CN103054796B discloses a cyclosporine micelle eye drop and a preparation method thereof, CN102210849A discloses a preparation method of a cyclosporine eye drop nanoparticle, and documents report a high-pressure homogeneous preparation technology of a cyclosporine submicron emulsion (preparation of cyclosporine a submicron emulsion for eyes, pharmaceutical journal of chinese hospital, vol 34, No. 18 in 2014).
Because the pathogenesis of dry eye is complex, monotherapy is incomplete, and with the popularization of dry eye knowledge and the increasing importance of people to it, many studies have demonstrated that inflammation plays an important role in the development of dry eye. The inflammatory reaction is one of the basic pathological changes or accompanying pathological changes of most eye diseases including dry eye, and other researches show that multiple anti-inflammatory drugs cooperate with cyclosporin to improve the blood concentration of cyclosporin in vivo by drug administration (cyclosporin A drug interaction and clinical application, Hebei medicine, 2016 (5) and 38 (9) th times), so that the cyclosporin eye drops have a broad prospect in combination with anti-inflammatory or antibiotic drugs for treating dry eye. The domestic cyclosporine eye drops (with the concentration of 1 percent) are clinically used for preventing and treating the immunological rejection reaction after the cornea transplantation, and the eye drops are an oil solvent preparation, are not easy to be compatible with tears, have strong irritation and poor drug cornea permeability, thereby influencing the dry eye treatment. Therefore, it is necessary to further explore novel preparations and compound preparations of cyclosporine to improve clinical compliance and effectiveness so as to meet the increasing national demand.
Patent CN101474397A discloses an injection containing cyclosporin a, dexamethasone injection and octreotide injection, which is a local injection for treating hyperthyroidism.
Patent CN103920138A discloses a pharmaceutical composition, a preparation and an application thereof, which combines rebamipide and cyclosporine A to generate a synergistic effect, and has a remarkable improvement (P <0.05) in the aspects of promoting tear secretion and clearing inflammation compared with the two when used independently.
Disclosure of Invention
The invention encounters difficulty in the process of preparing the nano suspension of the combination of the cyclosporine and the anti-inflammatory or antibiotic drugs, the nano suspension is a submicron colloid dispersion system formed by highly dispersing pure drug particles in a medium under the action of a small amount of stabilizing agent, the particle size is generally 10-1000nm, the specific area is large, the drug loading capacity is high, the solubility is high, and the problem of low drug bioavailability can be effectively solved. However, in the aspect of a cyclosporine ophthalmic compound preparation, the nanosuspension obtained by the conventional preparation method has the problems of interaction of two drugs, poor stability and the like.
The compound eye drops are prepared by combining the cyclosporine and the anti-inflammatory or antibiotic medicines, have good curative effect on xerophthalmia, and solve the difficulty in the preparation process through formula and process screening.
The invention aims to provide the cyclosporine compound eye drops, which can reduce the administration irritation, improve the drug absorption degree, realize the effect of synergistically treating xerophthalmia by utilizing the anti-inflammatory action of anti-inflammatory or antibiotic drugs and the immunosuppressive action of cyclosporine, and make up for the defects of the existing cyclosporine eye drops.
The invention provides a composition containing cyclosporine, which consists of cyclosporine and at least one other active ingredient, wherein the active ingredient is selected from one or more of anti-inflammatory drugs or antibiotic drugs.
Further, the weight ratio of the cyclosporine to the other active ingredient in the cyclosporine composition is 0.05-1: 0.02-1.
Still further, the anti-inflammatory or antibiotic drug is selected from: one or more of chloramphenicol, erythromycin, azithromycin, tobramycin, lincomycin, natamycin, clarithromycin, lincomycin hydrochloride, neomycin sulfate, gentamycin sulfate, streptomycin sulfate, tetracycline, rifampin, ofloxacin, levofloxacin hydrochloride, norfloxacin, enoxacin, ciprofloxacin hydrochloride, ciprofloxacin lactate, lomefloxacin hydrochloride, moxifloxacin hydrochloride, gatifloxacin, besifloxacin hydrochloride, tosufloxacin tosylate, pazufloxacin mesylate, flurbiprofen sodium, pranoprofen, indomethacin, diclofenac sodium, nepafenac, bromfenac sodium, ketorolac tromethamine, hydrocortisone acetate, prednisone acetate, dexamethasone sodium phosphate, sethoxytriphenon, and fluoromethalone.
Further, the anti-inflammatory or antibiotic drug is preferably selected from: one or more of azithromycin, moxifloxacin hydrochloride, indometacin, bromfenac sodium and dexamethasone sodium phosphate.
The invention further provides compound eye drops containing the cyclosporine composition, which are prepared from the cyclosporine composition, water for injection and pharmaceutically acceptable auxiliary materials, wherein the concentration of the cyclosporine is 0.05-1% (w/v), the concentration of anti-inflammatory or antibiotic drugs is 0.02-1% (w/v), the concentration of the pharmaceutically acceptable auxiliary materials is 0.24-15% (w/v), and the balance is oil for injection and water.
The pharmaceutically acceptable auxiliary materials are selected from: a surfactant at a concentration of 0.05-2% (w/v), a stabilizer at a concentration of 0.05-2% (w/v), a thickener at a concentration of 0.05-5%, an isotonicity adjusting agent at a concentration of 0.03-3% (w/v), and a pH adjusting agent at a concentration of 0.06-3% (w/v).
Further, the pharmaceutically acceptable excipients are selected from: a surfactant preferably at a concentration of 0.125-0.725% (w/v), a stabilizer preferably at a concentration of 0.45-1% (w/v), a thickener preferably at a concentration of 0.5-2%, an isotonicity adjusting agent preferably at a concentration of 0.43-1.75% (w/v), and a pH adjusting agent preferably at a concentration of 0.06-0.7% (w/v).
The surfactant is selected from: one or more of sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, sodium glycocholate, stearic acid, fatty glyceride, oleic acid, sodium oleate, sodium cholate, sodium deoxycholate, poloxamer, tween, span, lecithin and soybean lecithin.
Further, the surfactant is preferably selected from: one or more of stearic acid, poloxamer, tween, span and lecithin.
The stabilizer is selected from: one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, vitamin E, vitamin C, sodium nitrite, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate and disodium ethylenediamine tetraacetate.
Further, the stabilizer is preferably selected from: one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, vitamin C, and sodium sulfite
The thickening agent is selected from: dextrin and its derivatives, sodium alginate and its derivatives, sodium hyaluronate, glycerol, glucosamine polymer, chondroitin sulfate, acacia, tragacanth gum, guar gum, xanthan gum, chitosan, carbomer, and phytohemagglutinin. The isotonic regulator is selected from: one or more of mannitol, sorbitol, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, propylene glycol and glucose.
Further, the thickener is preferably selected from: sodium alginate and its derivatives, sodium hyaluronate, glycerol, and chondroitin sulfate.
The isotonic regulator is selected from: one or more of mannitol, sorbitol, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, propylene glycol and glucose;
further, the isotonicity adjusting agent is preferably selected from: one or more of mannitol, sorbitol, sodium chloride, potassium chloride, and glucose
The pH regulator is selected from: one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid and phosphoric acid.
Further, the pH adjusting agent is preferably selected from: one or more of boric acid, borax, citric acid, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
The invention further provides a preparation method of the compound cyclosporine eye drops, and the compound cyclosporine eye drops are prepared by the following steps:
(1) dissolving surfactant and cyclosporine in oil for injection to obtain a cyclosporine oil solution; dissolving anti-inflammatory or antibiotic drugs, a thickening agent, a stabilizing agent and an isotonic regulator in water to obtain an anti-inflammatory or antibiotic drug water solution;
(2) mixing the cyclosporine oil solution prepared in the step 1 with an anti-inflammatory or antibiotic medicine water solution to obtain a primary emulsion;
(3) homogenizing the primary emulsion under high pressure to obtain homogeneous emulsion, adjusting pH to 5.0-9.0, adding the rest water for injection, and sterilizing.
Further, the obtained preparation is a nano-emulsion with the average particle size of less than 1000 nm;
in another technical scheme, the cyclosporine compound eye drop is prepared by the following steps:
(1) dissolving surfactant in water for injection, filtering with filter membrane, adding cyclosporine, mixing, and preparing cyclosporine nanometer suspension by physical crushing technology;
(2) dissolving anti-inflammatory or antibiotic drug, thickener, stabilizer, and isotonic regulator in water for injection, and filtering with filter membrane to obtain anti-inflammatory or antibiotic drug water solution;
(3) uniformly mixing the cyclosporine nano suspension prepared in the step 1 with the anti-inflammatory or antibiotic medicine aqueous solution prepared in the step 2, adjusting the pH value to 5.0-9.0, and adding the balance of water for injection to obtain the pharmaceutical composition;
wherein, the physical crushing technology is one or two of a wet grinding technology and a high-pressure homogenizing technology which are used together.
The invention further provides application of the cyclosporine compound eye drops in preparation of a medicine for treating xerophthalmia.
The ciclosporin compound eye drops provided by the invention do not contain bacteriostatic agent, can be packaged in single dose, and the volume range of the packaged liquid medicine is 0.05-1.0 mL; the eye drop bottle with a filter device can also be used for multi-dose packaging, and the volume range of the packaged liquid medicine is 5-10 mL.
The technical core of the invention is that a nano suspension or emulsion is obtained by the preparation method of the invention through the proper proportioning combination of cyclosporine and anti-inflammatory or antibiotic medicines, wherein the proper proportioning enables the interaction between the medicines to disappear, thereby achieving the effect of mutual synergy, the anti-inflammatory or antibiotic medicines in the eye drops can relieve the inflammation of eyes, and the cyclosporine can adjust the related immunity, so the compounding of the cyclosporine and the anti-inflammatory or antibiotic medicines can obviously improve the drug effect, reduce the dosage of the cyclosporine, and simultaneously reduce the toxic and side effects. The results of lacrimal secretion and tear film rupture time experiments of the cyclosporine compound eye drops provided by the invention are superior to those of commercial Restasis eye drops, the obvious difference is achieved, the pharmacokinetic data is good, and the invention fully shows that the cyclosporine compound eye drops can improve the symptoms of xerophthalmia, increase the lacrimal secretion of xerophthalmia, stabilize the tear film and have the treatment effect on xerophthalmia. On the other hand, the preparation process conditions such as the temperature of condensed water, the suspension concentration, the type of a grinding medium or a homogenizing valve, the grinding speed or the homogenizing pressure, the grinding time or the homogenizing pass, the concentration of a surfactant and a stabilizer and the like are simultaneously controlled by screening auxiliary materials, so that the drug particles are effectively crushed or emulsified, the particles are prevented from agglomerating or demulsifying, and the cyclosporine nano suspension or emulsion with small particle size, uniform particle size, good dispersion and excellent stability is obtained.
The invention has the beneficial effects that:
1. the cyclosporine is combined with anti-inflammatory or antibiotic medicines for use, wherein the anti-inflammatory or antibiotic medicines relieve ocular inflammation, and meanwhile, the immunosuppressive effect of the cyclosporine is utilized, so that a good synergistic effect can be achieved, and the aim of effectively treating dry eyes is fulfilled.
2. The compound cyclosporin eye drops can increase the concentration of cyclosporin in tear fluid, prolong the residence time of drug in cornea, and improve the bioavailability of cyclosporin.
3. The cyclosporine compound eye drops can obviously promote the tear secretion of xerophthalmia and stabilize the tear film, and compared with the commercially available Restasis eye drops, the eye drops have better compliance and more obvious curative effect.
Description of the drawings:
FIG. 1 is a scanning electron micrograph of cyclosporine nanoparticles prepared in example 3
FIG. 2 is a scanning electron micrograph of a cyclosporin starting material
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1, preparation of 0.25% Cyclosporine Compound eye drops (nanosuspension)
Prescription
The preparation method comprises the following steps:
(1) weighing 65g of poloxamer, dissolving in 500mL of water for injection, adding 50g of cyclosporine, stirring and suspending uniformly, transferring into a wet grinding machine, grinding for 20min at 1500rpm by using a zirconia ball with the diameter of 0.6-0.8mm as a grinding medium to obtain a nano suspension, and testing the average particle diameter by using a particle size test to be 850 nm;
(2) weighing 100g moxifloxacin hydrochloride, 110g hydroxypropyl methylcellulose, 180g sorbitol, 85g boric acid and 55g borax, adding 4L of water for injection, stirring, dissolving and mixing uniformly, and filtering by a 0.22 mu m filter membrane to obtain an anti-inflammatory or antibiotic medicine aqueous solution;
(3) mixing the cyclosporine nano suspension prepared in the step (1) with the anti-inflammatory or antibiotic medicine aqueous solution obtained in the step (2), uniformly stirring, adjusting the pH to 5.0 by using borax borate, and then adding the balance of water for injection to 20L;
(4) and (4) detecting the liquid medicine obtained in the step (3), filling 0.2-0.4 mL of liquid medicine into a single-dose plastic packaging container in a hundred-grade environment after the liquid medicine is qualified, and sealing to obtain a finished product.
Example 2 preparation of 1% Cyclosporine Compound eye drops (nanosuspension)
Prescription
| Cyclosporin | 200g |
| Dexamethasone sodium phosphate | 4.0g |
| Span 80 | 145g |
| Polyvinylpyrrolidone K30 | 400g |
| Mannitol | 350g |
| Glycerol | 240g |
| Sodium hydroxide | Proper amount of |
| Water for injection | Adding to 20L |
The preparation method comprises the following steps:
(1) weighing 145g of span 80, dissolving in 1L of water for injection, adding 200g of cyclosporine, stirring and suspending uniformly, transferring into a wet grinding machine, grinding for 60min at 3000rpm by using a zirconia ball with the diameter of 0.6-0.8mm as a grinding medium to obtain a nano suspension, and testing the average particle diameter to be 450nm by using a particle size test;
(2) weighing 4.0g of dexamethasone sodium phosphate, 400g of polyvinylpyrrolidone K30, 350g of mannitol and 240g of glycerol, adding 10L of water for injection, stirring, dissolving, mixing uniformly, and filtering with 0.22 μm filter membrane to obtain an anti-inflammatory or antibiotic medicine aqueous solution;
(3) mixing the cyclosporine nano suspension prepared in the step (1) with the anti-inflammatory or antibiotic medicine aqueous solution obtained in the step (2), uniformly stirring, adjusting the pH value to 7.2 by using 1mol/L sodium hydroxide, and adding the balance of water for injection to 20L;
(4) and (4) detecting the liquid medicine obtained in the step (3), filling 0.5-1 mL of liquid medicine into a single-dose plastic packaging container in a hundred-grade environment after the liquid medicine is qualified, and sealing to obtain a finished product.
Example 3 preparation of 0.05% Cyclosporine Compound eye drops (nanosuspension)
Prescription
| Cyclosporin | 10g |
| Indometacin | 100g |
| Tween 80 | 25g |
| Polyethylene glycol 4000 | 90g |
| Sodium chloride | 86g |
| Citric acid | 12g |
| Sodium hyaluronate | 100g |
| Water for injection | Adding to 20L |
The preparation method comprises the following steps:
(1) weighing 25g of Tween 80, dissolving in 200mL of water for injection, adding 10g of cyclosporine, stirring and suspending uniformly, homogenizing at 1000bar under high pressure for 12 times to obtain a nano suspension, and testing the average particle size to be 235nm by using a particle size test; the particle distribution is narrower, 150-300nm, compared with the bulk drug particles, the bulk drug particles are larger, and the particle size distribution range is wider, 1-30 μm.
(2) Weighing 100g of indomethacin, 90g of polyethylene glycol 4000, 86g of sodium chloride and 12g of citric acid, adding 5L of water for injection, stirring, dissolving and uniformly mixing to obtain a medicinal water solution; weighing 100g of sodium hyaluronate, adding 5L of injection water to dissolve the sodium hyaluronate, stirring at the constant temperature of 50-70 ℃ for 12 hours to fully swell the sodium hyaluronate, and cooling to obtain a sodium hyaluronate solution; mixing the medicinal solution with sodium hyaluronate solution, stirring, and filtering with 0.22 μm filter membrane to obtain antiinflammatory or antibiotic medicinal aqueous solution;
(3) mixing the cyclosporine nano suspension prepared in the step (1) with the anti-inflammatory or antibiotic medicine aqueous solution obtained in the step (2), uniformly stirring, adjusting the pH to 9.0 by using citric acid, and then adding the balance of water for injection to 20L;
(4) and (4) detecting the liquid medicine obtained in the step (3), filling 10mL of liquid medicine into an eye drop bottle with a bacteria filtering device in a hundred-grade environment after the liquid medicine is qualified, and sealing to obtain a finished product.
EXAMPLE 4 preparation of 0.09% Cyclosporine Compound eye drops (emulsion)
Prescription
| Cyclosporin | 0.9g |
| Bromfenac sodium salt | 1.0g |
| Lecithin | 0.5g |
| Sodium nitrite | 0.5g |
| Sodium chloride | 0.3g |
| Glycerol | 50g |
| Sodium hydroxide | Proper amount of |
| Castor oil for injection | 55g |
| Water for injection | Adding to 1000mL |
The preparation method comprises the following steps:
(1) weighing 0.9g of cyclosporine and 0.5g of lecithin, adding 55g of castor oil for injection, stirring, dissolving and mixing uniformly to obtain a cyclosporine oil solution; weighing 1.0g of bromfenac sodium, 0.5g of sodium nitrite and 50g of glycerol, adding 900mL of water for injection, stirring, dissolving and uniformly mixing to obtain an anti-inflammatory or antibiotic medicine aqueous solution;
(2) mixing the cyclosporine oil solution prepared in the step (1) with an anti-inflammatory or antibiotic medicine aqueous solution, and carrying out high-speed shearing emulsification at 5000rpm for 2min to obtain a primary emulsion;
(3) homogenizing the primary emulsion prepared in the step (2) for 6 times at 800bar under high pressure to obtain uniform emulsion, adjusting the pH value of the uniform emulsion to 7.5 by using 1mol/L sodium hydroxide, and adding the balance of water for injection to 1000 mL;
(4) and (4) performing moist heat sterilization on the liquid medicine obtained in the step (3) at the temperature of 121 ℃ for 15min, cooling, filling 5mL of liquid medicine into an eye drop bottle with a bacterial filtering device, and sealing to obtain a finished product.
EXAMPLE 5 preparation of 0.2% Cyclosporine Compound eye drops (emulsion)
Prescription
| Cyclosporin | 2g |
| Azithromycin | 10g |
| Stearic acid | 20g |
| Vitamin C | 10g |
| Glucose | 30g |
| Sodium alginate | 20g |
| Sodium bicarbonate | 30g |
| Castor oil for injection | 80g |
| Water for injection | Adding to 1000mL |
The preparation method comprises the following steps:
(1) weighing 2.0g of cyclosporine and 20g of stearic acid, adding 80g of castor oil for injection, stirring, dissolving and mixing uniformly to obtain a cyclosporine oil solution; weighing 10g of azithromycin, 10g of vitamin C and 20g of sodium alginate, adding 900mL of water for injection, stirring, dissolving and mixing uniformly to obtain an anti-inflammatory or antibiotic medicine aqueous solution;
(2) mixing the cyclosporine oil solution prepared in the step 1 with an anti-inflammatory or antibiotic medicine aqueous solution, and carrying out high-speed shearing emulsification at 5000rpm for 2min to obtain a primary emulsion;
(3) homogenizing the primary emulsion prepared in the step 2 at 800bar under high pressure for 6 times to obtain uniform emulsion, adjusting the pH value of the uniform emulsion to 9.0 by using sodium bicarbonate, and adding the balance of water for injection to 1000 mL;
(4) and (4) performing moist heat sterilization on the liquid medicine obtained in the step (3) at 121 ℃ for 15min, cooling, filling 5mL of liquid medicine into an eye drop bottle with a bacterial filtering device, and sealing to obtain a finished product.
Example 6 dissolution test in vitro of Cyclosporine Compound eye drops
10mL of the 0.05% cyclosporin compound eye drops prepared in example 3 was weighed into a dialysis bag (8000 + 14000 relative to molecular cut-off), sealed and placed in a dissolution basket containing 900mL artificial tears, released at 37 ℃ and 75rpm, sampled at 20min, 40min, 1h, 2h, 4h, 6h, 8h, 12h and 24h for 2mL, and supplemented with the same volume of artificial tears at the same temperature. The content of cyclosporin in the release medium was calculated by high performance liquid chromatography, and the cumulative release amount was calculated, and the results are shown in table 1.
TABLE 1 dissolution rate results of cyclosporin compound eye drops
| Time of day | Dissolution (%) |
| 20min | 12.3±1.7 |
| 40min | 20.4±1.5 |
| 1h | 25.6±2.1 |
| 2h | 31.3±1.9 |
| 4h | 39.6±2.2 |
| 6h | 44.7±1.8 |
| 8h | 50.3±2.0 |
| 12h | 61.5±2.3 |
| 24h | 86.0±1.3％ |
The results in table 1 show that the dissolution rate of the ciclosporin compound eye drops in 24 hours is about 86%, which indicates that the sustained-release effect is good.
Example 7 tear pharmacokinetics study of Cyclosporine Compound eye drops
The 0.05% cyclosporin compound eye drops prepared in example 3 were compared with commercially available 0.05% cyclosporin emulsion eye drops (Restasis). Taking 108 healthy New Zealand white rabbits (2.0-3.0kg), dividing male and female rabbits into two groups without limitation, and administering different preparations to two eyes. Dripping compound eye drop and Restasis eye drop into conjunctival sac of domestic rabbit with micro sampler, respectively, administering 50 μ L per eye, and administering once more after 90s interval. After dropping the eye, respectively absorbing the tears of the rabbits at 20min, 40min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h and 96h by using filter paper, adding 100 mu L of methanol into a centrifugal tube, vortexing for 5min, and extracting the medicine. Centrifuging at 12000rpm for 10min, collecting supernatant 20 μ L, and performing high performance liquid phase analysis.
Adopting Kinetica software to fit a compartment model to the cyclosporine concentration and time data in tears, and calculating the pharmacokinetic parameters of the measured data of each test group: area under the time curve AUC, time to peak TmaxPeak reaching concentration CmaxEliminating half-life period T1/2(see Table 2). According to tear pharmacokinetic data, the peak reaching time of the two is consistent, and the AUC and C of the compound eye drop groupmaxAnd T1/2Significantly greater than Restasis group, AUCinfAbout 1.79 times, CmaxAbout 2.59 times, T1/2About 2.28 times, which shows that the compound eye drop can increase the concentration of the cyclosporine in tears, prolong the detention time of the cyclosporine before the cornea and achieve the purpose of improving the bioavailability of the cyclosporine in eyes.
TABLE 2 tear pharmacokinetic parameters after Compound eye drops and commercially available Restasis
EXAMPLE 8 pharmacodynamic study of Cyclosporine Compound eye drops
8.1 establishment of Dry eye model
A dry eye model is established by a method that a New Zealand white rabbit is given 50 mu L of 1% atropine sulfate 3 times per day to both eyes at 8:00am, 1:00pm and 6:00pm every day, the eyes of each group of white rabbits are checked 3 days before the experiment, and the white rabbits with eye irritation symptoms, corneal defects and conjunctival injuries are not used for the experiment.
8.2 modes of administration
No treatment is carried out after the administration of the model group, and the white rabbits in the drug group are respectively given corresponding eye drops 5min after the administration. The administration was continued for 7 days.
8.3 determination of ocular surface indices
8.3.1 tear secretion assay (SIT): schirmer experiments reflect tear secretion. The assay was performed at 0d and 7d after atropine sulfate administration. The white rabbits were placed in a room of moderate brightness and humidity, and Schirmer paper (5mm x 35mm) was reverse folded at the 5mm of the head end and placed at the junction of the posterior and middle portions 1/3 of the lower eyelid. The paper strip is taken out after the white rabbit closes the eye for 5min, and the length (mm) of the tear-soaked part test paper is measured after the white rabbit is dried for 30s at room temperature.
8.3.2 tear film Break Up Time (BUT): BUT reflects the stability of the tear film. Measurements were performed at 0d and 7d before and after dosing. Fluorescein is dropped into the eye, the tear film before the cornea is observed by a slit lamp, black spots appear to show tear film rupture, and the time until dry spots appear is the BUT value.
8.4 study on synergy pharmacodynamics of cyclosporine compound eye drops
8.4.1 animal grouping and Pre-staging
96 healthy New Zealand white rabbits (2.0-3.0kg, with unlimited males and females) were randomly divided into 16 groups, the 1 st group was a dry eye model group, and the rest groups were shown in Table 3.
TABLE 3 Cyclosporine compound eye drop synergistic pharmacodynamics study group
8.4.2 synergistic pharmacodynamic evaluation comparison of compound eye drops
The results of the tear secretion and tear film rupture time tests are shown in tables 4-5, and the results are shown. In 7 days, the compound eye drops containing anti-inflammatory or antibiotic medicines with different concentrations have very significant difference compared with the eye drops containing cyclosporine alone. And with the increase of the concentration of anti-inflammatory or antibiotic drugs, the amount of lacrimal secretion is increased, and the rupture time of the lacrimal film is prolonged. The results fully show that the self-made nano composite preparation can play a role in synergy, more effectively improve the symptoms of the xerophthalmia, increase the tear secretion of the xerophthalmia and stabilize the tear film, and has better treatment effect on the xerophthalmia than the single use of cyclosporine.
Table 4 SIT values of compound eye drops with different formulations (n ═ 6)
TABLE 5 BUT values of Compound eye drops with different formulations (n ═ 6)
8.5 pharmacodynamic evaluation comparison of Compound eye drops and Restasis eye drops on the market
8.5.1 animal grouping and Pre-staging
36 healthy New Zealand white rabbits (2.0-3.0kg, with unlimited sexes) were randomly divided into 6 groups, the group 1 was a dry eye model group, the group 2 was a drug-free blank control group prepared by the method of example 3, the group 3 was a Restasis eye drop control group, the group 4 was the compound eye drop prepared in example 3, the group 5 was the compound eye drop prepared by the method of example 3 and containing 0.05% of cyclosporin and 1% of indomethacin, and the group 6 was the compound eye drop prepared by the method of example 3 and containing 1% of cyclosporin and 0.02% of indomethacin
8.5.2 pharmacodynamic study of Compound eye drop and Restasis eye drop on the market
The results of tear secretion and tear film disruption time experiments are shown in tables 6 and 7. The results show that at 7 days, the blank group and the model group have no significant difference, the self-prepared group and the blank group have very significant difference, and the self-prepared group and the Restasis eye drop control group have significant difference. The results fully show that the self-made nano composite preparation can improve the symptoms of xerophthalmia, increase the tear secretion of xerophthalmia, stabilize the tear film and has good curative effect on xerophthalmia, and compared with the commercially available Restasis eye drops, the nano composite preparation has more obvious drug effect.
Table 6 SIT values for model group, Restasis control group, self-made group and blank control group (n ═ 6)
Table 7 BUT values of BUT (n ═ 6) for the model group, Restasis control group, self-made group and blank control group
Claims (6)
1. A compound eye drop of cyclosporin, wherein it is prepared from composition containing cyclosporin and acceptable supplementary product in pharmacy; the pharmaceutically acceptable auxiliary materials comprise water for injection;
the composition containing the cyclosporine consists of the cyclosporine and at least one other active ingredient, wherein the active ingredient is selected from one or the combination of more than two of anti-inflammatory or antibiotic medicines;
the anti-inflammatory or antibiotic medicine is selected from one or more of indomethacin, moxifloxacin hydrochloride and dexamethasone sodium phosphate;
the weight ratio of the cyclosporine to the other active component is 0.05-1: 0.02-1.
2. An ophthalmic solution according to claim 1, characterized in that the concentration of cyclosporin is 0.05-1% (w/v) and the concentration of the other active ingredient is 0.02-1% (w/v), said pharmaceutically acceptable excipients being selected from: a surfactant at a concentration of 0.05-2% (w/v), a stabilizer at a concentration of 0.05-2% (w/v), a thickener at a concentration of 0.05-5%, an isotonicity adjusting agent at a concentration of 0.03-3% (w/v), a pH adjusting agent at a concentration of 0.06-3% (w/v), and the balance water or oil for injection and water.
3. An ophthalmic solution according to claim 2 wherein the pharmaceutically acceptable excipient is selected from: a surfactant at a concentration of 0.125-0.725% (w/v), a stabilizer at a concentration of 0.45-1% (w/v), a thickener at a concentration of 0.5-2%, an isotonicity adjusting agent at a concentration of 0.43-1.75% (w/v), and a pH adjusting agent at a concentration of 0.06-0.7% (w/v).
4. An ophthalmic solution according to claim 3,
the surfactant is selected from: one or more of sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, sodium glycocholate, stearic acid, fatty glyceride, oleic acid, sodium oleate, sodium cholate, sodium deoxycholate, poloxamer, tween, span, lecithin and soybean lecithin;
the stabilizer is selected from: one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, vitamin E, vitamin C, sodium nitrite, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate and disodium ethylenediamine tetraacetate;
the thickening agent is selected from: dextrin and its derivatives, sodium alginate and its derivatives, sodium hyaluronate, glycerol, glucosamine polymer, chondroitin sulfate, acacia, tragacanth gum, guar gum, xanthan gum, chitosan, carbomer, and phytohemagglutinin;
the isotonic regulator is selected from: one or more of mannitol, sorbitol, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, propylene glycol and glucose;
the pH regulator is selected from: one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid and phosphoric acid.
5. The preparation method of the ciclosporin compound eye drops as claimed in claim 2, characterized in that the ciclosporin compound eye drops is prepared by the following steps:
(1) dissolving surfactant and cyclosporine in oil for injection to obtain a cyclosporine oil solution; dissolving anti-inflammatory or antibiotic drugs, a thickening agent, a stabilizing agent and an isotonic regulator in water to obtain an anti-inflammatory or antibiotic drug water solution;
(2) mixing the cyclosporine oil solution prepared in the step 1 with an anti-inflammatory or antibiotic medicine water solution to obtain a primary emulsion;
(3) homogenizing the primary emulsion under high pressure to obtain uniform emulsion, adjusting pH, adding the rest water for injection, and sterilizing;
the obtained preparation is a nano-emulsion;
or, the ciclosporin compound eye drops are prepared by adopting the following steps:
(1) dissolving a surfactant in water for injection, filtering with a filter membrane, adding cyclosporine, mixing uniformly, and preparing a cyclosporine nano suspension by adopting a physical crushing technology;
(2) dissolving anti-inflammatory or antibiotic medicine, thickener, stabilizer, and isoosmotic adjusting agent in water for injection, and filtering with filter membrane to obtain anti-inflammatory or antibiotic medicine water solution;
(3) uniformly mixing the cyclosporine nano suspension prepared in the step (1) with the anti-inflammatory or antibiotic medicine aqueous solution prepared in the step (2), adjusting the pH value of the mixture, and adding the balance of water for injection to obtain the pharmaceutical composition;
wherein, the physical crushing technology is one or two of a wet grinding technology and a high-pressure homogenizing technology which are used together.
6. The use of cyclosporin compound eye drops of claim 1 in the preparation of a medicament for treating dry eye.
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| CN115671256B (en) * | 2021-07-30 | 2024-04-09 | 四川大学华西医院 | Use of cyclosporin A in combination with diquafosol sodium for the preparation of a medicament for the treatment of dry eye |
| CN115869254A (en) * | 2021-09-29 | 2023-03-31 | 成都瑞沐生物医药科技有限公司 | Antibiotic eye preparation and preparation method and application thereof |
| KR102640323B1 (en) * | 2021-11-30 | 2024-02-27 | 대우제약 주식회사 | Stable nanosuspension of cyclosporine |
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